Drug therapies and hope for the future

Modulators are a fairly new development in the CF world. They are a very incredible and specialised group of therapies that actually somewhat rectify the underlying cause of CF by addressing the particular defect in the CFTR protein.

If you’ve read my post on what causes CF, you’ll remember that depending on the mutations that a person has, there are different ways that the CFTR protein is defective:

- Some mutations, such as the A455E mutation, interfere with the cell’s ability to read the instructions correctly or result in a degradation of the CFTR protein either of which means that very low/inadequate amounts of CFTR protein are made.

- Some mutations, such as G155D, make the protein correctly but there is an issue with the gating activity of the protein. Where this is the case, the CFTR protein is made and transported to the cell surface, but the gates do not open correctly to permit the movement of chloride ions between cells.

- Other mutations, such as F508del, make the protein but it is not folded correctly and so cannot be transported to the surface of the cell where it performs its function of moving chloride ions between cells.

- And finally, some nonsense or rare mutations don’t make the CFTR protein at all and so sadly Modulator therapies are not available for those that carry these mutations.

There are three main types of CFTR modulators are as follows: potentiators, correctors, and amplifiers below is an overview of how these help:

- CFTR potentiators address the defect in mutations such as G155D by holding open a key gate within the protein in a correct conformation long enough to facilitate the transport of chloride ions across the channel. Kalydeco (ivacaftor) is a CFTR potentiator developed by Vertex Pharmaceuticals.

- CFTR correctors are aimed at overcoming folding defects within the CFTR protein. This is what is needed for mutations such as F508del. However for mutations such as this they have found that combining a potentiator with a corrector can improve CFTR activity and reduce CF symptoms. So Orkambi (an ivacaftor/lumacaftor combination) was developed by Vertex and as a treatment for CF patients with two F508del CFTR mutations. And Symkevi (an ivacaftor/tezacaftor combination), has also been developed by Vertex for those over 12 years old with two copies of F508del and those with one copy of F508del as well as certain other mutations.

- CFTR amplifiers are intended for mutations such as A455R to enhance the amount/quantities of functional CFTR protein present on the cell surface. When used in combination with other modulators, amplifiers can make more CFTR available for the other modulators to act upon. PTI-428 is an investigational first-generation CFTR amplifier by Proteostasis Therapeutics, which is being tested as a single and combination therapy for CF.

Then this brings us on to ‘Next generation modulators’ - these are triple combination therapies that combine all of the above to create the best results for those with CF.

Kaftrio, made by Vertex, is a next-generation combination of three CF medications: elexacaftor, tezacaftor, and ivacaftor. It helps defective CFTR proteins work more effectively. Both elexacaftor and tezacaftor work as correctors, helping the faulty protein fold correctly. Ivacaftor is a potentiator, holding the channel open so that more salt can pass through it. Trikafata has been proven to result in significant improvements in lung function, sweat chloride (which is a measure of how well chloride and water are moving between cells), and a number of other metrics. Kaftrio is currently only available for those over 12 with cystic fibrosis (and is limited to those with 2 copies of F508del - or with one copy of F508del and certain other mutations.)

So there’s many reasons to be positive as a CF mama but this brings me on to three very crucial points:

- Kaftrio is not a cure, it brings many side effects and for some people it inexplicably does not work (even if they meet the ‘perfect criteria’ of having two copies of the F508del mutation). There are no guarantees it will work for someone with CF and until Arlo is taking it and we can see it is making a difference, I will not be pinning all my hopes on it.

- Kaftrio - or any equivalent - is not available to around 10% of the CF population who have rare/nonsense mutations. These people and their families are patiently waiting for their ‘wonder drug’ and whilst they do we must continue to fight for them and support them as they try to manage the debilitating nature of CF (especially later in life).

- Whilst CF babies are unable to take modulators (as we wait for them to be old enough to do so), we have to work tirelessly to try and keep their little lungs safe and prevent any irreversible damage from being made. We still have to ‘fight’ every day (physio at least twice a day, prophylactic medication, vitamin supplements, extra calories, hospital visits, pharmacy trips (and more trips to collect missing items!), cough swabs, poo samples/photos, the list goes on for many families with a baby with CF.

So please, if you can skip tomorrow’s coffee and make a donation to my fundraising page, it will mean the world to us and really will make a difference to a community that needs to continue looking for a cure!

https://justgiving.com/fundraising/le-big-jog (link in footer)